Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

BACKGROUND: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. OBJECTIVE: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. METHODS: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. RESULTS: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003). CONCLUSIONS: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

BACKGROUND: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 µg/L) and underwent bone marrow biopsy during their ICU course. RESULTS: Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.

Fatal pulmonary hemorrhage, pneumothorax and skin necrosis caused by IRIS to an Aspergillus flavus infection in a young patient with metamizole associated agranulocytosis.

We report the case of a young female with steroid-dependent ulcerative colitis (UC) who developed a complex systemic infection with Aspergillus flavus. This occurred following a UC relapse while vacationing in the Middle East, leading to extended use of metamizole and subsequent agranulocytosis. On her return to Germany, she was hospitalized for neutropenic sepsis and later transferred to our hospital due to persistent cytopenia and suspected Hemophagocytic Lymphohistiocytosis (HLH). Despite initial stabilization with targeted treatment for pulmonary Aspergillus flavus infection, her condition rapidly deteriorated following the onset of an Immune Reconstitution Inflammatory Syndrome (IRIS), which manifested as skin necrosis and pneumothorax after the replenishment of neutrophil granulocytes. The patient eventually died from an unmanageable pulmonary hemorrhage. Microscopy of skin necroses showed a massive presence of Aspergillus flavus, but tissue culture remained negative, suggesting effective antifungal treatment yet delayed phagocytosis due to agranulocytosis. This case underscores the need to consider IRIS in immunosuppressed patients who worsen despite aggressive and appropriately targeted treatment, highlighting its potential beyond the commonly recognized context in HIV-positive patients.

Clinical features and prognostic risk prediction of adult hemophagocytic lymphohistiocytosis: a 9-year retrospective study.

Hemophagocytic lymphohistiocytosis (HLH) has a low incidence and high mortality. In order to improve our understanding of the clinical features and prognostic risk factors of adult HLH, we analyzed the clinical characteristics and prognostic risk factors of adult HLH and developed a prognostic model to predict the overall survival (OS) of adult HLH. The clinical characteristics and survival statistics of adult patients with HLH identified at The Second Affiliated Hospital of Chongqing Medical University between February 2012 and October 2020 were retrospectively analyzed to constitute the primary cohort, while patients between 25 October 2020 and 20 March 2023 were collected at the same institution as a validation cohort for the prospective study. A total of 142 patients met the inclusion criteria, with 72 and 70 in the primary cohort and validation cohort respectively. In the primary cohort, the median OS was 102 days, with 37.5%, 34.5%, and 28.7% 1-, 2-, and 3-year OS, respectively. Univariate analysis showed that age, interleukin-10 (IL-10), interleukin-2 receptor (IL-2R), prothrombin time (PT), and indirect bilirubin (IBiL) were correlated with prognosis. Multivariate analysis showed that IL-10 and PT were independent factors affecting OS in adult patients with HLH. A prognostic model consisting of IL-2R, PT, and IL-10 and a corresponding prognostic nomogram were developed adopting the principle of minimum value of Akaike information criterion(AIC). The model has a high prediction accuracy letter (C-index = 0.708). The AUC values of 1-year, 2-year, and 3-year were 0.826, 0.865, and 0.882, correspondingly. In the validation cohort, all patients were divided into high-risk and low-risk groups, and the risk of death was significantly higher in the high-risk group than in the low-risk group (p < 0.01). The calibration curve for the model shows that the Nomogram constructed in this study is very reliable to predict the OS of HLH patients. IL-10 and PT have significant prognostic value in adult HLH. The prognostic model and the nomogram built in this study can forecast the OS of adult HLH patients.

Hemophagocytic lymphohistiocytosis secondary to virus infection and followed by lupus nephritis recurrence in a renal transplantation pediatric recipient: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by systemic inflammation and organ failure as a result of dysregulated immune cell activation. HLH can be induced by a variety of factors including infection, tumours and autoimmune disease and can also occur in patients following solid organ transplantation. Occurrence of HLH and lupus nephritis (LN) successively within a short period of time after renal transplantation is uncommon. CASE PRESENTATION: We described an 11-year-old female post-transplant patient who presented with hemocytopenia, fever, elevated serum ferritin, splenomegaly, hyperlipidemia, and hypofibrinemia, and was clinically diagnosed with HLH. After comprehensive treatment with corticosteroids, intravenous immunoglobulin (IVIG), and reducing immunosuppressants, her condition improved, but then hematuria ensued. The transplant kidney biopsy showed LN. She was treated with hydroxychloroquine and methylprednisolone while intensive immunosuppressive agents were given. She has remained in remission for two years until now. CONCLUSIONS: The main inducing factors of HLH should be identified as early as possible, and accurate treatment plans should be taken. The long-course IVIG regimen may be one of the effective treatments for virus-induced HLH. After remission of HLH, we need to be alert to the recurrence of autoimmune diseases in patients with underlying diseases, and timely increase immunosuppressants.

The superiority of Epstein-Barr virus DNA in plasma over in peripheral blood mononuclear cells for monitoring EBV-positive NK-cell lymphoproliferative diseases.

Epstein-Barr virus (EBV), characterized as an omnipresent virus, has been found able to infect NK cells and leads to NK-cell type EBV-positive lymphoproliferative diseases (EBV-NK-LPDs). We retrospective analyzed 202 EBV-NK-LPDs (including 64 CAEBV-NK, 27 aggressive natural killer-cell leukemia (ANKL), and 111 extranodal NK/T-cell lymphoma (ENKTL)) patients' relationships between EBV DNA copies laboratory test results and clinical features. In CAEBV-NK cohort, EBV DNA loads in either plasma or PBMCs had significant differences between the active state and the inactive state. Receiver operating characteristic curves were used to measure the diagnosis accuracy of EBV DNA copies. After comparing the area under the curve, EBV DNA loads in plasma had significantly higher accuracy in distinguishing disease activation than in PBMCs. Therefore, we propose redefining CAEBV-NK diagnosis criteria as increased EBV DNA copies in plasma (over 7.1 × 102 copies/ml) instead of in peripheral blood. In ANKL and ENKTL cohorts, patients who received effective therapy had significantly lower EBV DNA copies in plasma & PBMCs than in those with ineffective therapy. The significant and consistent decline indicated EBV DNA loads in plasma being a more sensitive biomarker in monitoring EBV-NK-LPDs therapy responses. Hemophagocytic lymphohistiocytosis (HLH) can occur secondary to EBV-NK-LPDs, mostly associated with a poor prognosis, so we try to estimate the combination of HLH by monitoring EBV DNA copies. When comparing the Receiver operating characteristic curves of EBV DNA copies, EBV DNA loads in plasma had higher diagnosis accuracy. When the copies level over 4.16 × 103 copies/ml, it might indicate combining with HLH.

Prolonged fever and pancytopenia in a case of severe dengue may be secondary hemophagocytic lymphohistiocytosis.

The diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in the setting of dengue fever is usually challenging but should be kept in mind in patients with persistent fever, pancytopenia, and multiorgan dysfunction. We report a case of severe dengue who had prolonged fever with multiorgan involvement, laboratory features fulfilling the diagnostic criteria of HLH, and had a prompt response with high-dose corticosteroids. Physicians should be aware of this rare clinical syndrome and its variable clinical presentations so that fatal outcomes can be prevented with prompt and appropriate treatment.

Diagnostic Challenges in Pediatric Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation that encompasses a broad range of underlying genetic diseases and infectious triggers. Monogenic conditions, autoimmune diseases, and infections can all drive the phenotype of HLH and associated immune hyperactivation with hypercytokinemia. A diagnosis of HLH usually requires a combination of clinical and laboratory findings; there is no single sensitive and specific diagnostic test, which often leads to "diagnostic dilemmas" and delays in treatment initiation. Ferritin levels, one of the most commonly used screening tests, were collected across a large tertiary care pediatric hospital to identify the positive predictive value for HLH. Herein, we present several cases that illustrate the clinical challenges of confirming an HLH diagnosis. Additionally, we report on the utility of establishing a formal multi-disciplinary group to aid the prompt diagnosis and treatment of patients presenting with HLH-like pathophysiologies.

Ehrlichia-induced hemophagocytic lymphohistiocytosis after autologous stem cell transplant.

Hemophagocytic lymphohistiocytosis (HLH) causes multiorgan failure due to the release of multiple cytokines mediating widespread inflammation. We present a patient with multiple myeloma on maintenance chemotherapy with the anti-CD38 monoclonal antibody daratumumab after autologous stem cell transplant (ASCT) who developed fatal HLH secondary to Ehrlichiosis.

Hemophagocytic lymphohistiocytosis and thrombotic microangiopathy after parvovirus B19 infection and renal transplantation: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease characterized by hyperactivation of the immune system that causes hypercytokinemia and potentially multi organ failure. HLH can occur in patients with underlying rheumatic or autoinflammatory disorders. Additionally, HLH can develop in patients during infections or malignancies without a known genetic predisposition. CASE PRESENTATION: We herein report a patient, who presented with fever, both acute kidney and liver injury, anemia, thrombocytopenia and HSV stomatitis. HLH was diagnosed based on clinical criteria and qPCR revealed an acute parvovirus B19 infection as potential underlying infectious trigger. Treatment was started with both IVIG and dexamethasone. Subsequently, kidney biopsy demonstrated TMA. CONCLUSIONS: In rare cases both HLH and aHUS can occur simultaneously in a patient as a consequence of viral infections. Insights from this unusual case might help physicians understand this complex symptom constellation.

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500 ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. OBJECTIVE AND METHODS: We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10-year period, with serum ferritin >5000 ng/mL, were included. RESULTS: Among 1055 patients with serum ferritin >5000 ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70 398 ng/mL (SD 122 908), median 40 019 ng/mL (IQR 16 051-68 326). The prevalence of HLH only reached 50% as serum ferritin approached 90 000 ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16 000 ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). CONCLUSIONS: The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH.

Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare though often fatal hyperinflammatory syndrome mimicking sepsis in the critically ill. Diagnosis relies on the HLH-2004 criteria and HScore, both of which have been developed in pediatric or adult non-critically ill patients, respectively. Therefore, we aimed to determine the sensitivity and specificity of HLH-2004 criteria and HScore in a cohort of adult critically ill patients. METHODS: In this further analysis of a retrospective observational study, patients ≥ 18 years admitted to at least one adult ICU at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with hyperferritinemia of ≥ 500 µg/L were included. Patients' charts were reviewed for clinically diagnosed or suspected HLH. Receiver operating characteristics (ROC) analysis was performed to determine prediction accuracy. RESULTS: In total, 2623 patients with hyperferritinemia were included, of whom 40 patients had HLH. We found the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity). By adjusting HLH-2004 criteria cutoffs of both hyperferritinemia to 3000 µg/L and fever to 38.2 °C, sensitivity and specificity increased to 97.5% and 96.1%, respectively. Both a higher number of fulfilled HLH-2004 criteria [OR 1.513 (95% CI 1.372-1.667); p <  0.001] and a higher HScore [OR 1.011 (95% CI 1.009-1.013); p <  0.001] were significantly associated with in-hospital mortality. CONCLUSIONS: An HScore cutoff of 168 revealed a sensitivity of 100% and a specificity of 94.1%, thereby providing slightly superior diagnostic accuracy compared to HLH-2004 criteria. Both HLH-2004 criteria and HScore proved to be of good diagnostic accuracy and consequently might be used for HLH diagnosis in critically ill patients. CLINICAL TRIAL REGISTRATION: The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Epstein-Barr virus-related hemophagocytic lymphohistiocytosis complicated with coronary artery dilation and acute renal injury in a boy with a novel X-linked inhibitor of apoptosis protein (XIAP) variant: a case report.

BACKGROUND: X-linked lymphoproliferative disease (XLP) is a rare inherited X-linked primary immunodeficiency diseases (PID). One such disease, X-linked inhibitor of apoptosis protein (XIAP) deficiency, is characterized by Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH). However, EBV-HLH with coronary artery dilation and acute renal injury (AKI) in children is unusual. CASE PRESENTATION: We report the case of a young boy aged 17 months with a novel XIAP variant. He was initially diagnosed with EBV-HLH based on the HLH-2004 diagnostic criteria and the condition was accompanied by coronary artery dilation and acute renal injury. The comprehensive genetic analysis of peripheral blood-derived DNA revealed a hemizygous variant of the XIAP gene [c.116G > C(p.G39A)], which was inherited from his mother (heterozygous condition). After combined treatment with rituximab, intravenous immunoglobulin, corticosteroids, antiviral drugs, and mycophenolate mofetil (MMF) in addition to supportive therapy, his clinical manifestations and laboratory indexes were improved. The patient achieved complete remission with MMF treatment in the 8-month follow-up. CONCLUSIONS: We report the [c.116G > C(p.G39A)] variant in the XIAP gene for the first time in a case of XLP-2 associated with EBV-HLH. For male patients with severe EBV-HLH, the possibility of XLP should be considered and molecular genetic testing should be used early in auxiliary diagnosis. Reports of EBV-HLH with coronary artery dilation and AKI in children are rare. In the patients with EBV-HLH, color Doppler echocardiography and urine tests should be monitored regularly. If necessary, renal biopsy can be performed to clarify the pathology. Treatment with rituximab, immunosuppressors and supportive therapy achieved a good effect, but long-term follow-up is required.

A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.

Dual Threat of Epstein-Barr Virus: an Autopsy Case Report of HIV-Positive Plasmablastic Lymphoma Complicating EBV-Associated Hemophagocytic Lymphohistiocytosis.

Epstein-Barr virus (EBV) reactivation causes serious diseases in immunocompromised hosts, such as acquired immunodeficiency syndrome (AIDS). We report on a case of plasmablastic lymphoma (PBL) with hemophagocytic lymphohistiocytosis (HLH).A-53-year-old Japanese man was diagnosed with PBL and AIDS. In addition to combined antiretroviral therapy, HyperCVAD (cyclophosphamide, doxorubicin, vincristine, prednisone)/high-dose methotrexate + cytarabine was initiated immediately. Partial remission was attained with chemotherapy. However, the patient developed HLH and died despite intensive therapy. Autopsy findings suggested that PBL was controlled, and immunosuppression appeared to cause fatal infection. The patient showed high titers of EBV viral-capsid antigen (VCA)-IgG (1:2560) on PBL diagnosis and high EBV-DNA levels throughout the clinical course. Moreover, EBV-DNA was detected in the fraction of CD8-positive cells, which strongly supports the pathogenesis of EBV-associated HLH.Our report highlights the importance of EBV control in patients with EBV-positive AIDS lymphoma. EBV not only behaves as the etiologic pathogen of PBL but also can be a trigger of HLH, the fatal complication. Careful follow-up of the EBV status should be performed, and if needed, preemptive anti-EBV therapy should also be considered to prevent EBV-associated complications such as HLH.

Autoimmune hemolytic anemia: An unusual presentation of hemophagocytic lymphohistiocytosis in a pediatric post-liver transplant patient.

Hemophagocytic lymphohistiocytosis (HLH), a rare condition characterized by immune dysfunction with uncontrolled activation of macrophages and hypersecretion of cytokines, has only been reported in a small number of pediatric patients following solid organ transplant (SOT). The diagnosis of HLH after SOT is especially difficult, as several of the diagnostic criteria, including fever, splenomegaly, and cytopenias, are nonspecific and can be seen with other post-transplant complications. Autoimmune hemolytic anemia (AIHA) has also been reported after pediatric SOT and is thought to be related to immunosuppression, specifically tacrolimus. Although HLH and AIHA have been separately described following SOT, there have been no reports of them occurring together in post-liver transplant (LT) patients. We report the first case of autoimmune hemolysis as the presenting symptom of HLH in a pediatric post-LT patient.

A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). CASE PRESENTATION: Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. CONCLUSIONS: Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

Interferon gamma and interleukin 10 polymorphisms in Chinese children with hemophagocytic lymphohistiocytosis.

AIM: The aim of the study is to investigate the association of interferon gamma (IFN-γ) and interleukin-10 (IL-10) gene single nucleotide polymorphisms with the susceptibility of hemophagocytic lymphohistiocytosis (HLH) in Chinese children without known family history of HLH. PROCEDURE: Forty children with HLH and 160 age- and gender-matched healthy controls from Xuzhou Children's Hospital were enrolled in the study. Serum IFN-γ and IL-10 levels were measured by enzyme linked-immunosorbent assay. Polymorphisms of the IFN-γ gene at position +874 and +2109, and IL-10 at position -1082 were analyzed by allele-specific PCR. RESULT: Median serum concentrations of IFN -γ and IL-10 were significantly higher in children with HLH compared to healthy controls. The frequencies of IFN-γ +874 T/A and T/T genotypes, as well as T allele, were significantly higher in the HLH group compared with those in the control group. The frequencies of IL-10 -1082 G/A genotype and G allele were significantly increased in HLH patients compared with healthy controls. No significant difference was found in the distribution of IFN-γ +2109G/A genotypes between children with HLH and controls. CONCLUSION: This study presents preliminary evidence for the association between IFN +874 T/A, T/T, IL-10 -1082 A/G genotypes, and HLH susceptibility in Chinese children with HLH.

A Case of Refractory Langerhans Cell Histiocytosis Complicated with Hemophagocytic Lymphohistiocytosis Rescued by Cord Blood Transplantation with Reduced-intensity Conditioning.

　We diagnosed a female infant with Langerhans cell histiocytosis (LCH) who was refractory to conventional chemotherapy. She showed refractory inflammation that was complicated with hemophagocytic lymphohistiocytosis (HLH) during LCH chemotherapy; therefore, we changed the protocol to HLH2004 (dexamethasone, cyclosporine A and VP16). However, there were no signs of hematological recovery. We therefore performed cord blood transplantation with reduced-intensity conditioning, and she achieved complete remission for over 2 years. As salvage therapy for refractory LCH, hematopoietic stem cell transplantation may be a good therapeutic choice, especially when LCH is complicated with HLH.

[Hemophagocytic lymphohistiocytosis : A diagnostic challenge on the ICU]. / Hämophagozytische Lymphohistiozytose : Diagnostische Herausforderung auf der ITS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T­cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease. Missed or late diagnosis is believed to be a major cause of the high mortality. OBJECTIVES: To describe the current knowledge on HLH and to raise awareness. MATERIALS AND METHODS: Analysis of case reports, current studies, and expert recommendations. RESULTS: Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with a clinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. A promising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. CONCLUSIONS: Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.